Submissions for variant NM_032634.4(PIGO):c.3118G>A (p.Val1040Ile)

gnomAD frequency: 0.00003  dbSNP: rs149439295

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001080844	SCV000479866	uncertain significance	Hyperphosphatasia with intellectual disability syndrome 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000421736	SCV000514119	likely benign	not provided	2021-01-14	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae	RCV001080844	SCV000652698	likely benign	Hyperphosphatasia with intellectual disability syndrome 2	2023-12-27	criteria provided, single submitter	clinical testing
New York Genome Center	RCV001080844	SCV001431201	uncertain significance	Hyperphosphatasia with intellectual disability syndrome 2	2020-05-07	criteria provided, single submitter	clinical testing
Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center	RCV001080844	SCV004037344	uncertain significance	Hyperphosphatasia with intellectual disability syndrome 2	2020-01-24	criteria provided, single submitter	clinical testing	The c.3118G>A variant in the PIGO gene is missense variant, which results in the substitution of a conserved valine residue at amino acid position 1040 for an isoleucine (NP_116023.2). This variant localizes to coding exon 10 of the PIGO gene (11 coding exons in total; NM_032634.4). In silico predictors for this variant are not consistent: It is predicted to be neutral to protein structure and/or function by PROVEAN, but is predicted to be damaging by SIFT. This variant was reported in Genome Aggregation Database (gnomAD) with an allelic frequency of 0.0325% (92 out of 282,864 alleles). This variant is reported in ClinVar with three submissions of conflicting interpretation of pathogenicity, with two laboratories classifying it as a variant of uncertain clinical significance and one variant classifying it as likely benign (Variation ID# 366753). To the best of our knowledge, this specific variant has not been reported in the literature. Given this evidence, the c.3118G>A, p.Val1040Ile variant in PIGO is considered a variant of uncertain clinical significance. Parental studies were not conducted at our laboratory, but this variant was reported to be paternally inherited at another laboratory in a separate pregnancy of same parents (2019).
PreventionGenetics, part of Exact Sciences	RCV003392220	SCV004119466	uncertain significance	PIGO-related disorder	2022-10-13	criteria provided, single submitter	clinical testing	The PIGO c.3118G>A variant is predicted to result in the amino acid substitution p.Val1040Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.65% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-35089399-C-T), which is likely too frequent for a pathogenic variant. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.